Our work, over 19 years ago, shows progressive telomere shortening in human cells during senescence, lead to the proposal that telomerase inhibition may block the growth of tumors. We followed up on this idea by generating a telomerase null mouse and over the past 12 years us, and others, have shown that indeed short telomeres limit the growth of some tumor types. In addition, we found that paradoxically, in some settings, short telomeres may initiate tumor formation. To help resolve this paradox and develop more sophisticated approaches to telomerase inhibition in cancer, we are studying the mechanism and pathways that are activated when telomeres become critically short. In this proposal we will focus on the mechanism by which short telomeres block the growth of B-cell lymphoma. We will identify the specific genes that signal from a critically short telomere, through p53 to block cell growth. We will take advantage of the powerful E-mu-myc mTR-/- G5 mice that we developed in the previous period with funding from the NCI PPG. Using this tumor model and shRNA libraries, we will identify tumor suppressor genes that may specifically respond to short telomeres. We will also examine the recombination mechanisms by which a subset of tumors with short telomeres escape and grow in the absence of telomerase.